The present invention relates to certain pyrrolo-, thieno-, furano-and pyrazolo-[3,4-d]pyridazinones, processes for their preparation, pharmaceutical compositions containing them, a process for preparing the pharmaceutical compositions, and methods of treatment involving their use.
In accordance with the present invention, there is provided a compound of the general formula 
wherein B represents a group CH or a nitrogen (N), sulfur (S) or oxygen (O) atom; D represents a carbon (C) or nitrogen (N) atom; E represents a group CR3 or a nitrogen (N) atom; when D is a carbon atom, then B is a sulfur or oxygen atom and E is a group CR3, and when D is a nitrogen atom, then either B is a group CH and E is a group CR3 or a nitrogen atom, or B is a nitrogen atom and E is a group CR3; R1 represents a group NRxe2x80x2Rxe2x80x3 where Rxe2x80x2 represent a hydrogen atom or a C1-C6 alkyl group, Rxe2x80x3 represents a C1-C6 alkyl group, or Rxe2x80x2 and Rxe2x80x3 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated heterocyclic ring, or R1 represents a C1-C6 alkyl, C1-C6 alkoxy, C1-C3-alkyloxyC1-C3-alkyl, C3-C6-cycloalkyloxyC1-C3-alkyl, C3-C6 alkenyl, phenyl, C3-C7 cycloalkyl, C3-C5 cycloalkylmethyl or C3-C7 cycloalkenyl group, each of which may be optionally substituted by one or more halogen atoms; R2 represents a methyl group, or a C2-C6 alkyl group optionally substituted by a C1-C6 alkoxy group other than in the 1-position; R3 represents a hydrogen atom or a group Xxe2x80x94R5 or Xxe2x80x94Ar1; X represents a group xe2x80x94Oxe2x80x94, S(O)n, SO2N(R6) or C(xe2x95x90O)N(R6); n is 0, 1 or 2; R5 represents an optionally substituted alkyl or alkenyl group, or, additionally, in the case where X represents SO2N(R6) or C(xe2x95x90O)N(R6), R5 and R6 together with the nitrogen atom to which they are attached may form an optionally substituted 3- to 7-membered heterocyclic ring; Ar1 represents an optionally substituted phenyl or pyridyl group; R6 represents a hydrogen atom, C1-C6 alkyl or is linked to R5 as defined above; R4 represents a group CHR7Ar2 or Ar3 or, additionally, in the case where D represents a carbon atom, a group C(O)Ar2 or CR7(OH)Ar2; Ar2 represents an aryl or heteroaryl group which may be optionally substituted; Ar3 represents an acenaphthenyl, indanyl or fluorenyl group, each of which may be optionally substituted; and R7 represents a hydrogen atom or a C1-C4 alkyl group; or a pharmaceutically-acceptable salt or solvate thereof.
In the present specification, unless otherwise indicated, an alkyl or alkenyl substituent or an alkyl moiety in an alkoxy, alkoxycarbonyl, (di)alkylamino, acylamino, alkylsulfonamido, alkylamido or (di)alkylsulfamoyl substituent group may be linear or branched. Furthermore, the alkyl moieties in a dialkylamino or dialkylsulfamoyl substituent group may be the same or different.
R1 represents a group NRxe2x80x2Rxe2x80x3 where Rxe2x80x2 represent a hydrogen atom or a C1-C6 alkyl, preferably C1-C4 alkyl, group, Rxe2x80x3 represents a C1-C6 alkyl, preferably C1-C4 alkyl, group, or Rxe2x80x2 and Rxe2x80x3 together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated heterocyclic ring, or R1 represents a C1-C6, preferably C3-C5, alkyl group (e.g. propyl, isopropyl, butyl or isobutyl), a C1-C6 alkoxy group (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy or hexoxy), C1-C3-alkyloxyC1-C3-alkyl (e.g. xe2x80x94CH2xe2x80x94Oxe2x80x94CH3), C3-C6-cycloalkyloxyC1-C3-alkyl (e.g. xe2x80x94CH2xe2x80x94O-cyclopropyl, xe2x80x94CH2xe2x80x94O-cyclobutyl or xe2x80x94CH2xe2x80x94O-cyclopentyl), a C3-C6 alkenyl group (e.g. propenyl or butenyl), a phenyl group, a C3-C7, preferably C3-C5, cycloalkyl group (e.g. cyclopropyl, cyclobutyl or cyclopentyl), a C3-C5 cycloalkylmethyl group (e.g. cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl), or a C3-C7, preferably C3-C5, cycloalkenyl group (e.g. cyclopropenyl, cyclobutenyl or cyclopentenyl, each of which may be optionally substituted by one or more, preferably one to four, e.g. one or two, halogen atoms (e.g. fluorine or chlorine). Where R1 groups contain a double bond the first carbon atom of the R1 group cannot be part of the olefin.
R2 represents a methyl group, or a C2-C6, preferably C2-C4, alkyl group optionally substituted by a C1-C6, preferably C1-C4, alkoxy group (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy or isobutoxy) other than in the 1-position. Thus, the alkoxy substituent, if present, is attached to a carbon atom other than the carbon atom which is directly bonded to the ring nitrogen atom.
R3 represents a hydrogen atom or a group Xxe2x80x94R5 or Xxe2x80x94Ar1.
X represents a group xe2x80x94Oxe2x80x94, S(O)n where n is 0, 1 or 2 or a group SO2N(R6) or C(xe2x95x90O)NR6. Preferably X represents a group xe2x80x94Oxe2x80x94, S(O)n where n is 0, 1 or 2, or a group C(xe2x95x90O)NR6.
The group R5 represents an optionally substituted alkyl or alkenyl group, or, additionally, in the case where X represents SO2N(R6) or C(xe2x95x90O)N(R6), R5 and R6 together with the nitrogen atom to which they are attached may form an optionally substituted 3- to 7-membered heterocyclic ring. If R5 represents an optionally substituted alkyl group, the alkyl group will preferably contain from 2 to 10, particularly from 2 to 6, carbon atoms or if R5 represents an optionally substituted alkenyl group, the alkenyl group will preferably contain from 3 to 10, particularly from 3 to 6, carbon atoms. R5 groups cannot form enamines or enol ethers. The alkyl or alkenyl group or heterocyclic ring may be substituted preferably by one or more, e.g. one, two, three or four, substituents independently selected from amido, amino, carboxyl, cyano, hydroxyl, C1-C6 alkoxy (preferably C1-C4 alkoxy), C1-C6 alkylthio (preferably C1-C4 alkylthio), C1-C6 alkylcarbonyl (preferably C1-C4 alkylcarbonyl), Cl-C6 alkoxycarbonyl (preferably C1-C4 alkoxycarbonyl), C3-C7 cycloalkyl (preferably C5-C6 cycloalkyl), (di) C1-C6 alkylamino (preferably (di)methylamino or (di)ethylamino), C2-C6 acylamino (preferably C2-C4 acylamino), Cl-C6 alkylsulfonamido (preferably C1-C4 alkylsulfonamido), tetrahydrofuranyl, dioxolanyl, imidazolyl, haloC1-C6alkylsulfonamido and tetrazolyl. Especially preferred substituent groups are hydroxyl, carboxyl, methoxy, methylthio, methylcarbonyl, cyclopentyl, xe2x80x94NHC(O)CH3, tetrahydrofuranyl, dioxolanyl and imidazolyl groups.
Ar1 represents an optionally substituted phenyl or pyridyl group. The phenyl or pyridyl group may be substituted preferably by one or more, e.g. one to four, substituents independently selected from carboxyl, hydroxyl, C2-C6, preferably C2-C4, acylamino, C1-C6, preferably C1-C4, alkylamido, C1-C6, preferably C1-C4, alkylsulfonamido and (di)C1-C6, preferably C1-C4, alkylsulfamoyl. The group Ar1 is preferably a pyridyl, particularly 2-pyridyl, group.
R4 represents a group CHR7Ar2 or Ar3 or, additionally, in the case where D represents a carbon atom, a group C(O)Ar2 or CR7(OH)Ar2. R4 is preferably a group CHR7Ar2, C(O)Ar2 or CR7(OH)Ar2.
R7 represents a C1-C4 alkyl group (e.g. methyl or ethyl) or, most preferably, a hydrogen atom.
Ar2 represents an aryl or heteroaryl group which may be optionally substituted. Examples of suitable aryl and heteroaryl groups include phenyl, naphthyl, pyridyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, thienyl, benzothienyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, indolyl, indolizinyl, pyrazolyl, indazyl, imidazolyl, benzimidazolyl, imidazopyridyl, triazolyl, benzotriazolyl and triazolopyridyl. C
The Ar2 group may be optionally substituted by one or more, preferably one to four, especially one to three, substituent groups independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), trifluoromethyl, trifluoromethoxy, amino, cyano, carboxyl, nitro, C1-C6, preferably C1-C4, alkyl, C1-C6, preferably C1-C4, alkoxy, (di)C1-C6, preferably C1-C4, alkylamino, C2-C6, preferably C2-C4, acylamino, C1-C6, preferably C1-C4, alkylsulfonamido, CONHxe2x80x94(C1-C6, preferably C1-C4, alkyl), and C1-C6, preferably C1-C4, alkoxycarbonyl.
Ar2 is preferably a phenyl, naphthyl, pyridyl, quinolinyl or imidazopyridyl group which may be optionally substituted by one to three substituents independently selected from halogen, cyano, trifluoromethyl and C1-C6 alkoxy (especially methoxy).
Ar3 represents an acenaphthenyl, indanyl or fluorenyl group, each of which may be optionally substituted by one or more, e.g. one to four, substituent groups. The optional substituents may be the same as those for Ar2.
Preferred compounds of the invention include:
2,6-Dihydro-2-methyl-4-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyridazin-1-one,
2,6-Dihydro-2-(2-methoxyethyl)4-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyridazin-1-one,
2,6-Dihydro-7-[(3-hydroxypropyl)thio]-2-methyl-4-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4 d]pyridazin-1-one,
4-{[2,6-Dihydro-2-methyl-4-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1-oxo-1H-pyrrolo[3,4-d]pyridazin-7-yl]thio}butanoic acid,
2,6-Dihydro-7-[(3-hydroxypropyl)sulfinyl]-2-methyl-4-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyridazin-1-one,
2,6-Dihydro-7-[(3-hydroxypropyl)sulfonyl]-2-methyl-4-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyridazin-1-one,
2-[1-Hydroxy-1-(1-naphthalenyl)methyl]-5-methyl-7-(2-methylpropyl)thieno[2,3-d]pyridazin-4(5H)-one,
5-Methyl-7-(2-methylpropyl)-2-(1-naphthalenylmethyl)thieno[2,3-d]pyridazin-4(5H)-one,
3-[(3-Hydroxypropyl)thio]-5-methyl-7-(2-methylpropyl)-2-(1-naphthalenylmethyl)-thieno[2,3-d]pyridazin-4(5H)-one,
5-Methyl-7-(2-methylpropyl)-2-(1-naphthalenylcarbonyl)thieno[2,3-d]pyridazin-4(5H)-one,
3-[(3-Hydroxypropyl)sulfinyl]-5-methyl-7-(2-methylpropyl)-2-(1-naphthalenyl-methyl)thieno[2,3-d]pyridazin-4(5H)-one,
4{[4,5-Dihydro-5-methyl-7-(2-methylpropyl)-2-(1-naphthalenylmethyl)-4-oxothieno[2,3-d]pyridazin-3-yl]thio}butanoic acid,
5-Methyl-7-(2-methylpropyl)-2-(1-naphthalenylmethyl)-3-(2-pyridinylthio)thieno[2,3-d]pyridazin-4(5H)-one,
3-[(3-Hydroxypropyl)sulfonyl]-5-methyl-7-(2-methylpropyl)-2-(1-naphthalenyl-methyl)thieno[2,3-d]pyridazin-4(5H)-one,
2-[1-Hydroxy-1-phenylmethyl]-5-methyl-7-(2-methylpropyl)thieno[2,3-d]pyridazin-4(5H)-one,
5-Methyl-7-(2-methylpropyl)-2-phenylmethylthieno[2,3-d]pyridazin-4(5H)-one,
3-[(3-Hydroxypropy)thio)]-5-methyl-7-(2-methylpropyl)-2-phenylmethylthieno[2,3-d]pyridazin-4(5H)-one,
3-[(3-Hydroxypropyl)sulfonyl]-5-methyl-7-(2-methylpropyl)-2-phenylmethylthieno-[2,3-d]pyridazin-4(5H)-one,
2,6-Dihydro-2-methyl-4-(2-methylpropyl)-6-phenylmethyl-1H-pyrrolo[3,4-d]pyridazin-1-one,
2,6-Dihydro-2-methyl-4-(2-methylpropyl)-6-phenylmethyl-7-(2-pyridinylthio)-1H-pyrrolo[3,4-d]pyridazin-1-one,
2,6-Dihydro-7-[(3-hydroxypropyl)thio]-2-methyl-4(2-methylpropyl)-6-phenylmethyl-1H-pyrrolo[3,4-d]pyridazin-1-one,
2,6-Dihydro-2-methyl-4-(2-methylpropyl)-6-(3,4,5-trimethoxyphenyl)methyl-1H-pyrrolo[3,4-d]pyridazin-1-one,
2,6-Dihydro-2-methyl-6-(1-naphthalenylmethyl)-4(1-methylethyl)amino-1H-pyrrolo[3,4-d]pyridazin-1-one,
2,6-Dihydro-2-methyl-4(2-methylpropyl)-6-(4-pyridinyl)methyl-1H-pyrrolo[3,4-d]pyridazin-1-one,
6-(2-Chlorophenyl)methyl-2,6-dihydro-2-methyl-4-(2-methylpropyl)-1H-pyrrolo[3,4-d]pyridazin-1-one,
6-(3,5-Difluorophenyl)methyl-2,6-dihydro-2-methyl-4-(2-methylpropyl)-1H-pyrrolo[3,4-d]pyridazin-1-one,
6-(2-Chloro-6-fluorophenyl)methyl-2,6-dihydro-2-methyl-4-(2-methylpropyl)-1H-pyrrolo[3,4-d]pyridazin-1-one,
6-(3-Chloro-2-fluorophenyl)methyl-2,6-dihydro-2-methyl-4-(2-methylpropyl)-1H-pyrrolo[3,4-d]pyridazin-1-one,
2,6-Dihydro-2-methyl-4-(2-methylpropyl)-6-(2-quinolinylmethyl)-1H-pyrrolo[3,4-d]pyridazin-1-one,
2,6-Dihydro-2-methyl-4-(2-methylpropyl)-6-(2-trifluoromethylphenyl)methyl-1H-pyrrolo[3,4-d]pyridazin-1-one,
2,6-Dihydro-6-(2-imidazo[1,2-a]pyridinyl)methyl-2-methyl-4-(2-methylpropyl)-1H-pyrrolo[3,4-d]pyridazin-1-one,
2,6-Dihydro-N-[3-(1-1H-imidazolyl)propyl]-2-methyl-4-(2-methylpropyl)-1-oxo-6-phenylmethyl-1H-pyrrolo[3,4-d]pyridazin-1-one-5-carboxamide,
2,5-Dihydro-5-methyl-7-(2-methylpropyl)-2-(1-naphthalenylmethyl)-4H-pyrazolo[3,4-d]pyridazin-4-one,
2,6-Dihydro-6-methyl-4-(2-methylpropyl)-2-(1-naphthalenylmethyl)-7H-pyrazolo[3,4-d]pyridazin-7-one,
2,5-Dihydro-3-[(3-hydroxypropyl)thio]-5-methyl-7-(2-methylpropyl)-2-(1-naphthalenylmethyl)-4H-pyrazolo[3,4-d]pyridazin-4-one,
2-[1-Hydroxy-1-(1-naphthalenyl)methyl]-5-methyl-7-(2-methylpropyl)furo[2,3-d]pyridazin-4(5H)one,
5-Methyl-7-(2-methylpropyl)-2-(1-naphthalenylmethyl)furo[2,3-d]pyridazin-4(5H)one,
2-[1-Hydroxy-1-(3-cyanophenyl)methyl]-5-methyl-7-(2-methylpropyl)furo[2,3-d]pyridazin-4(5H)one,
2-(3-Cyanophenyl)methyl-5-methyl-7-(2-methylpropylfuro[2,3-d]pyridazin-4(5H)one,
2-(2-Trifluoromethylphenyl)methyl-5-methyl-7-(2-methylpropy)thieno[2,3-d]pyridazin-4(5H)-one,
2-[(1-Hydroxy-1-pyridin-3-yl)methyl]-5-methyl-7-(2-methylpropyl)thieno[2,3-d]pyridazin-4(5H)-one hydrochloride,
5-Methyl-7-(2-methylpropyl)-2-(3-pyridinylmethyl)thieno[2,3-d]pyridazin-4(5H)-one,
2-(2-Chloro-6-fluorophenyl)methyl-5-methyl-7-(2-methylpropyl)thieno[2,3-d]pyridazin-4(5H)-one,
2-[(1-Hydroxy-1-quinolin-3-yl)methyl]-5-methyl-7-(2-methylpropyl)thieno[2,3-d]pyridazin-4(5H)-one,
5-Methyl-7-(2-methylpropyl)-2-(3-quinolinylmethyl)thieno[2,3-d]pyridazin-4(5H)-one hydrochloride,
2-(3-Chlorophenyl)methyl-3-(2-hydroxyethoxy)-7-(methoxymethyl)-5-methylthieno[2,3-d]pyridazin-4(5H)-one,
2-[(3-Chlorophenyl)methyl]-7-cyclohexyl-3-(2-hydroxyethoxy)-5-methylthieno[2,3-d]pyridazin-4(5H)-one,
2-[(3-Chlorophenyl)methyl]-3-(2-hydroxyethoxy)-5-methyl-7-phenylthieno[2,3-d]pyridazin-4(5H)-one,
2-[(3-Chlorophenyl)methyl]-7-cyclopentyl-3-(2-hydroxyethoxy)-5-methylthieno[2,3-d]pyridazin-4(5H)-one,
7-Cyclopropylmethyl-3-methoxy-5-methyl-2-[(3-trifluoromethylphenyl)methyl]thieno[2,3-d]pyridazin-4(5H)-one,
7-Cyclopropylmethyl-5-methyl-3-[2-(methylthio)ethoxy]-2-[(3-trifluoromethylphenyl)methyl]thieno[2,3-d]pyridazin-4(5H)-one,
7-Cyclopropylmethyl-3-(2-methoxyethoxy)5-methyl-2-[(3-trifuoromethyl-phenyl)methyl]thieno[2,3-d]pyridazin-4(5H)-one,
3-Cyclopentylmethoxy-7cyclopropylmethyl-5-methyl-2-[(3-trifluoromethyl-phenyl)methyl]thieno[2,3-d]pyridazin-4(5H)-one,
7-Cyclopropylmethyl-5-methyl-3-(tetrahydrofuran-2-ylmethoxy)-2-[(3-trifluoromethylphenyl)methyl]thieno[2,3-d]pyridazin-4(5H)-one,
7-Cyclopropylmethyl-3-(3-hydroxy-3methyl-butoxy)-5-methyl-2-[(3-trifluoromethyl-phenyl)methyl]thieno[2,3-d]pyridazin-4(5H)-one,
N-{(3-[7-Cyclopropylmethyl-5-methyl-4-oxo-2-[(3-trifluoromethylphenyl)methyl]-4,5-dihydrothieno[2,3-d]pyridazin-3-yl]oxypropyl}acetamide,
7-Cyclopropylmethyl-3-([1,3]dioxolan-4-ylmethoxy)-5-methyl-2-[(3-trifluoromethyl-phenyl)methyl]thieno[2,3-d]pyridazin-4(5H)-one, and
7-Cyclopropylmethyl-5-methyl-3-(4oxopentyl)oxy-2-[(3-trifluoromethyl-phenyl)methyl]thieno[2,3-d]pyridazin-4(5H)-one.
The present invention further provides a process for the preparation of a compound of formula (I) as defined above which comprises:
(a) when X represents S(O)n and n is 1 or 2, oxidising a compound of general formula 
wherein R3 represents Sxe2x80x94R5 or Sxe2x80x94Ar1 and B, D, R1, R2, R4, R5 and Ar1 are as hereinbefore defined, in the presence of an appropriate quantity of a suitable oxidising agent (e.g. 3-chloroperoxybenzoic acid or potassium peroxymonosulfate, commercially sold under the trade mark xe2x80x9cOXONExe2x80x9d) and an appropriate organic solvent (e.g. dichloromethane) under conditions which are well known to those skilled in the art; or
(b) when X represents S(O)n and n is 0, reacting a corresponding compound of formula (I) in which E is CR3 and R3 is a hydrogen atom, with a compound of general formula (III), R8xe2x80x94Sxe2x80x94Sxe2x80x94R8, when the groups R8 both represent R5 or Ar1 as previously defined, or with a compound of general formula (IV), Lxe2x80x94Sxe2x80x94R8, wherein L represents a leaving group such as an arylsulfinate group and R8 is as defined above, in the presence of lithium diisopropylamide (LDA) at a temperature from xe2x88x9278xc2x0 C. to ambient temperature (20xc2x0 C.); or
(c) when X represents SO2N(R6), reacting a compound of general formula 
wherein Lxe2x80x2 represents a leaving group such as a halogen atom (e.g. chlorine) and B, D, R1, R2 and R4 are as defined above, with a compound of general formula (VI), HNR6R8, wherein R6 and R8 are as hereinbefore defined, e.g. in an aqueous solution of sodium hydrogen carbonate; or
(d) when X represents C(xe2x95x90O)N(R6), reacting a compound of general formula 
wherein B, D, R1, R2 and R4 are as hereinbefore defined with a compound of formula (VI) as defined above, in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenzotriazole hydrate in the presence of a solvent such as dimethylformamide; or
(e) when D is a carbon atom, E is CR3, R3 is a hydrogen atom and R4 is CH(OH)Ar2, reacting a compound of general formula 
wherein B, R1 and R2 are as hereinbefore defined, with a compound of general formula (IX), Ar2CHO, where Ar2 is as hereinbefore defined, in the presence of lithium diisopropylamide at xe2x88x9278xc2x0 C. to ambient temperature (20xc2x0 C.); or
(f) when D is a carbon atom, E is CR3, R3 is a hydrogen atom and R4 is CHR7Ar2, reducing a corresponding compound of formula (I) in which R4 is CR7(OH)Ar2 (e.g. as prepared in (e) above), in the presence of triethylsilane and trifluoroacetic acid; or
(g) when D is a carbon atom, E is CR3, R3 is a hydrogen atom and R4 is C(O)Ar2, oxidising a corresponding compound of formula (I) in which R4 is CH(OH)Ar2 as prepared in (e) above, e.g. in the presence of potassium permanganate; or
(h) when D is a carbon atom, E is CR3, R3 is a hydrogen atom, R4 is CR7(OH)Ar2 and R7 is a C1-C4 alkyl group, reacting a corresponding compound of formula (I) in which R4 is C(O)Ar2 as prepared in (g) above, with a C1-C4 alkylating agent, e.g. a Grignard reagent such as a C1-C4 alkylmagnesium halide, in the presence of a solvent, e.g. tetrahydrofuran; or
(i) when D is a carbon atom, E is CR3, R3 is a hydrogen atom and R4 is Ar3, reacting a compound of formula (VIII) as hereinbefore defined, with 1-indanone, 2-indanone, 9-fluoreneone or 1-acenaphthenone, in the presence of lithium diisopropylamide and optionally cerium (III) chloride at xe2x88x9278xc2x0 C. to ambient temperature (20xc2x0 C.), followed by a reduction reaction, e.g. in the presence of triethysilane and trifluoroacetic acid; or
(j) when D is a nitrogen atom, B is CH, E is CR3 and R3 is a hydrogen atom, reacting a compound of general formula 
wherein R9 is an alkyl group (e.g. C1-C6 alkyl such as methyl) and R1 and R4 are as previously defined, with a compound of general formula (XI), R2NHNH2, wherein R2 is as previously defined, in the presence of a solvent such as ethanol under reflux conditions; or
(k) when D is a nitrogen atom, B is CH and E is a nitrogen atom, reacting a compound of general formula 
wherein R10 is an alkyl group (e.g. C1-C6 alkyl such as methyl) and R1 and R4 are as previously defined, with a compound of formula (XI) as previously defined, in the presence of a solvent such as ethanol under reflux conditions;
(l) when D is a nitrogen atom, B is a nitrogen atom, E is CR3 and R3 is a hydrogen atom, reacting a compound of general formula 
wherein R11 is an alkyl group (e.g. C1-C6 alkyl such as methyl) and R1 and R4 are as previously defined, with a compound of formula (XI) as previously defined, in the presence of a solvent such as ethanol under reflux conditions;
(m) when X is xe2x80x94Oxe2x80x94, reacting a compound of general formula 
wherein B, D, R1, R2 and R4 are as hereinbefore defined, with a compound of general formula (XIIIB), R8-Lxe2x80x3, wherein Lxe2x80x3 represents a leaving group such as a halogen atom and R8 is as defined above; or
(n) when D is a carbon atom, B is a sulfur or oxygen atom, R3 represents xe2x80x94OR5 and R4 represents CH2Ar2, reacting a compound of general formula (XIIIC) 
wherein Bxe2x80x2 represents asulfur or oxygen atom and R1, R5 and Ar2 are as hereinbefore defined, with a compound of formula (XI) as previously defined, in the presence of a solvent such as ethanol under reflux conditions;
and optionally thereafter converting the compound of formula (I) to a further compound of formula (I) and/or forming a pharmaceutically-acceptable salt or solvate of the compound of formula (I).
Compounds of formula (V) may conveniently be prepared by reacting a compound of formula (I) in which E is CR3 and R3 is a hydrogen atom, with sulfur dioxide and lithium diisopropylamide at xe2x88x9278xc2x0 C., followed by reaction with N-chlorosuccinimide in a solvent (e.g. a two-phase solvent system such as water/hydrochloric acid/dichloromethane).
Compounds of formula (VII) may be readily prepared by reacting a compound of formula (I) in which E is CR3 and R3 is a hydrogen atom, with carbon dioxide in the presence of lithium diisopropylamide.
Compounds of formula (X) may conveniently be prepared by reacting a compound of general formula 
wherein R1 and R9 are as defined above, with a compound of general formula 
wherein R4 is as hereinbefore defined, in the presence of silver fluoride and a suitable solvent such as acetonitrile.
Compounds of formula (X) where R4 is CH2Ar2 can alternatively be prepared from compounds of general formula 
where R1 and R9 are as previously defined, by reacting with a compound of formula (XVII), Ar2CH2Lxe2x80x2xe2x80x3 where Lxe2x80x2xe2x80x3 is a leaving group such as halogen and 2Ais as defined above. The reaction can be carried out in the presence of a base in a suitable solvent, for example sodium hydride/dimethylformamide (NaH/DMF), optionally in the presence of potassium iodide (KI).
Compounds of formula (XVI) can be prepared by reacting a compound of general formula 
in which R1 and R9 are as defined above, with tosylmethyl isocyanide. The reaction is suitably carried out in the presence of a base such as sodium hydride in a solvent mixture such as ether/dimethyl sulfoxide.
The preparation of compounds of formulae (XII) and (XIII) is described by the following reaction scheme in which Rxe2x89xa1R10xe2x89xa1R11, THF denotes tetrahydrofuran, DMF denotes dimethylformamide, Hal denotes a halogen atom and T denotes an intermediate: 
Compounds of formula (XIIIC) can be prepared according to the following reaction scheme: 
Compounds of formula (XIC) can be prepared according to the following reaction scheme: 
Compounds of formula (III), (IV), (VI), (VIII), (IX), (XI), (XIIIB), (XIV), (XV) and (XVIII) are either commercially available, are well known in the literature or may be prepared easily using known techniques.
Compounds of formula (I) can be converted into further compounds of formula (I) using standard procedures. For example, compounds of formula (I) where R5 represents a hydroxy-substituted alkyl group, e.g. xe2x80x94(CH2)3OH, can be converted to compounds of formula (I) where R5 represents a cyano-substituted alkyl group, e.g. xe2x80x94(CH2)3CN, by reaction with methanesulfonyl chloride (MsCl) in the presence of triethylamine and dichloromethane followed by reaction with sodium cyanide in the presence of dimethylformamide. The resulting compounds of formula (I) may in turn be converted into further compounds of formula (I) where R5 represents a tetrazolyl-substituted alkyl group by reaction with trimethyltin azide (Me3SnN3) in toluene under reflux conditions. These and other conversions are shown by way of illustration in the following reaction scheme in which xe2x80x98Alkxe2x80x99 denotes xe2x80x98alkylxe2x80x99 and xe2x80x98Halxe2x80x99 denotes xe2x80x98halogenxe2x80x99: 
It will be appreciated by those skilled in the art that in the process of the present invention certain functional groups such as hydroxyl or amino groups in the intermediate compounds may need to be protected by protecting groups. Thus, the final stage in the preparation of the compounds of formula (I) may involve the removal of one or more protecting groups.
The protection and deprotection of functional groups is described in xe2x80x98Protective Groups in Organic Chemistryxe2x80x99, edited by J. W. F. McOmie, Plenum Press (1973) and xe2x80x98Protective Groups in Organic Synthesisxe2x80x99, 2nd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).
The compounds of formula (I) above may be converted to a pharmaceutically-acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p-toluenesulfonate, or an alkali metal salt such as a sodium or potassium salt.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
The compounds of the invention are useful because they possess pharmacological activity in human and non-human animals. They are therefore indicated as pharmaceuticals for use in the (prophylactic) treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS). Examples of these conditions are:
(1) (the respiratory tract) reversible obstructive airways diseases including asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer""s lung and related diseases, fibroid lung and idiopathic interstitial pneumonia;
(2) (bone and joints) rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter""s disease), Behcet""s disease, Sjogren""s syndrome and systemic sclerosis;
(3) (skin) psoriasis, atopical dermatitis, contact dermatitis and other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia areata, allergic conjunctivitis and vernal conjunctivitis;
(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn""s disease, ulcerative colitis, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema;
(5) (other tissues and systemic disease) multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto""s thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia pupura;
(6) (allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease.
The compounds of the invention are also indicated for use as antimicrobial agents, and thus may be used in the treatment of diseases caused by pathogenic micro-organisms.
Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
In another aspect, the invention provides the use of a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
The invention further provides a method of effecting immunosuppression which comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined to a patient.
The invention still further provides a method of treating, or reducing the risk of, a reversible obstructive airways disease in a patient suffering from, or at risk of, said disease, is which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
The compounds of formula (I) and pharmaceutically-acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically-acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99%w (percent by weight), more preferably from 0.10 to 70%w, of active ingredient, and, from 1 to 99.95%w, more preferably from 30 to 99.90%w, of a pharmaceutically-acceptable adjuvant, diluent or carrier, all percentages by weight being based on total composition.
Thus, the present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined in association with a pharmaceutically-acceptable adjuvant, diluent or carrier.
The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined with a pharmaceutically-acceptable adjuvant, diluent or carrier.
The pharmaceutical composition of the invention may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally.
The present invention will be further understood from the following illustrative examples in which, unless otherwise specified, chromatography was carried out over silica and organic solutions were dried over magnesium sulfate. The terms GC, MS, NMR, CDCl3 and DMSO denote respectively gas chromatography, mass spectrometry, nuclear magnetic resonance, chloroform-d and dimethyl sulfoxide.